PROJECT SUMMARY/ABSTRACT The proposed K23 Career Development Award will enable Dr. Kevin Clerkin to establish an independent research career with expertise in the diagnosis and mechanism of cardiac allograft vasculopathy (CAV). Dr. Clerkin is a clinical advanced heart failure & transplant cardiologist, whose long-term goal is to optimize outcomes of heart transplant recipients with respect to CAV. However, further training is required to achieve that goal. As such, he has assembled a multidisciplinary team of mentors with individual expertise in: (1) transplant cardiology (2) transplant immunology (3) clinical trial design and conduct (4) multimodality cardiac imaging and (5) research dissemination. The career development plan includes formal coursework and mentored meetings in transplant immunology and clinical trial design. Additionally, it involves activities and mentored experiences in career development, research dissemination, and grantsmanship. Heart transplantation is the gold standard treatment for end-stage heart failure, afflicting ~250,000 Americans annually. Given that CAV is the cause of death for up to 1/3rd of transplant patients, it is necessary to improve our understanding and ability to diagnose CAV. The primary objective of this K23 research training is to improve diagnostics for CAV and identify mechanisms instigating early CAV in order to lay the groundwork for future studies to test therapies targeting that pathway. This proposal consists of two interrelated studies to achieve this objective through clinical and translational research. In the first, we hypothesize that physiology based screening (measuring coronary blood flow or coronary flow reserve [CFR]) will improve the diagnosis of CAV over traditional angiography. We also hypothesize that CFR measured on a non-invasive cardiac PET scan will correlate with CFR measured using a pressure wire during coronary angiography, thereby allowing for a new primarily non-invasive screening approach. In the second translational study we will leverage the careful CAV phenotyping of Study 1 to explore clonal hematopoiesis of indeterminate potential (CHIP) as a potential mechanism for early CAV. CHIP in adults has been associated with an increased risk of atherosclerosis, mediated by increased inflammatory macrophage chemokines and cytokines. While presently nothing is known of its impact on CAV, based on our previous work identifying populations of macrophages surrounding coronary arteries of patients retransplanted for CAV, we hypothesize that patients with CHIP will have an increased risk of CAV. Targeted gene sequencing will be performed on peripheral blood samples from patients in our biobank in an effort to detect the presence of CHIP and assess its association with early CAV. This K23 proposal will position Dr. Clerkin to accomplish his goals of 1) improving diagnosis of CAV, 2) identifying a novel target for optimizing CAV related patient outcomes post- heart transplant, and 3) facilitating his development into an independent investigator in the field of transplant cardiology.